moflomycin and Leukemia

In a previous study we reported that a new anthracycline derivative (moflomycin) exhibited a higher antileukemic activity compared to other anthracyclines, such as daunorubicin and doxorubicin. To explain the superior antileukemic effect of moflomycin and to disclose a possible structure-activity relationship, we investigated the three main mechanisms by which anthracyclines are though to exert their antitumor effect: DNA binding, free radical production and topoisomerase II inhibition. The DNA interaction was assessed both by DNA binding and DNA unwinding assays, free radical generation was studied by electron spin resonance, and topoisomerase II interaction by analysis of the stimulation of enzyme-induced DNA breaks. The results showed a higher free radical production and a greater stimulation of topoisomerase II-mediated DNA cleavage by moflomycin than doxorubicin, associated with a lower DNA affinity. The different biochemical characteristics of moflomycin, particularly its interaction with topoisomerase II, are related to the structural modifications performed on the chromophore. These properties, associated with a higher stability of the molecule induced by the presence of an iodine atom on the sugar moiety, are probably responsible for the higher antileukemic activity of this compound.

Topics: Antibiotics, Antineoplastic; Daunorubicin; DNA; DNA Damage; Electron Spin Resonance Spectroscopy; Enzyme Inhibitors; Free Radicals; Humans; Leukemia; Reactive Oxygen Species; Structure-Activity Relationship; Topoisomerase II Inhibitors

The mutagenicity of a new anthracycline (moflomycin) with potent antileukemic activity was studied by the Ames test in four strains of Salmonella typhimurium (TA97a, TA98, TA100 and TA102), and compared to the mutagenicity of doxorubicin, widely used as antineoplastic agent. Unlike doxorubicin, moflomycin displayed no mutagenic activity in strains TA98 and TA100. Low mutagenicity was only observed in TA102 strain and was not enhanced after metabolic activation. This result indicates that moflomycin induce mutagenicity by reverting base-pair substitution. The structural changes in the sugar moiety may be involved in the reduced mutagenicity of moflomycin. The low mutagenicity of moflomycin shown in this study enhances the potential advantage of this new derivative which displays a high antileukemic activity.

Topics: Antibiotics, Antineoplastic; Biotransformation; Daunorubicin; Doxorubicin; Leukemia; Mutagenicity Tests; Mutagens; Salmonella typhimurium